Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic alcohol consumption is known to increase the susceptibility to acute and chronic pancreatitis, and it is likely that a cofactor is required to initiate the progression to alcoholic pancreatitis. The severity and complications of alcoholic and nonalcoholic acute pancreatitis may be influenced by a number of cofactors, including endotoxemia. To explore the effect of a possible cofactor, we used endotoxin [lipopolysaccharide (LPS)] as a tool to induce cellular injury in the alcoholic pancreas. Single, increasing doses of endotoxin were injected in rats fed an alcohol or control diet and killed 24 h after the injection. We examined the mechanism by which LPS exacerbates pancreatic injury in alcohol-fed rats and whether the injury is associated with apoptosis or necrosis. We showed that chronic alcohol exposure alone inhibits apoptosis through the intrinsic pathway and the downstream apoptosis executor caspase-3 compared with the controls. Pancreatic necrosis and inflammation increased after LPS injection in control and alcohol-fed rats in a dose-dependent fashion but with a significantly greater response in the alcohol-fed animals. Caspase activities and TdT-mediated dUTP nick-end labeling positivity were lower in the alcoholic pancreas injected with LPS, whereas the histopathology and inflammation were more severe compared with the control-fed animals. Assessment of a putative indicator of necrosis, the ratio of ADP to ATP, indicated that alcohol exposure accelerates pancreatic necrosis in response to endotoxin. These findings suggest that the pancreas exposed to alcohol is more sensitive to LPS-induced damage because of increased sensitivity to necrotic cell death rather than apoptotic cell death. Similar to the liver, the pancreas is capable of responding to LPS with a more severe response in alcohol-fed animals, favoring pancreatic necrosis rather than apoptosis. We speculate that this mechanism may occur in acute alcoholic pancreatitis patients.
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PMID:Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis? 1597 89

Alcohol abuse is associated with both acute and chronic pancreatitis. Repeated episodes of acute pancreatitis or pancreatic injury may result in chronic pancreatitis. We investigated ethanol-induced pancreatic injury using a mouse model of binge ethanol exposure. Male C57BL/6 mice were exposed to ethanol intragastrically (5 g/kg, 25% ethanol w/v) daily for 10 days. Binge ethanol exposure caused pathological changes in pancreas demonstrated by tissue edema, acinar atrophy and moderate fibrosis. Ethanol caused both apoptotic and necrotic cell death which was demonstrated by the increase in active caspase-3, caspase-8, cleaved PARP, cleaved CK-18 and the secretion of high mobility group protein B1 (HMGB1). Ethanol altered the function of the pancreas which was indicated by altered levels of alpha-amylase, glucose and insulin. Ethanol exposure stimulated cell proliferation in the acini, suggesting an acinar regeneration. Ethanol caused pancreatic inflammation which was indicated by the induction of TNF-alpha, IL-1beta, IL-6, MCP-1 and CCR2, and the increase of CD68 positive macrophages in the pancreas. Ethanol-induced endoplasmic reticulum stress was demonstrated by a significant increase in ATF6, CHOP, and the phosphorylation of PERK and eiF-2alpha. In addition, ethanol increased protein oxidation, lipid peroxidation and the expression of iNOS, indicating oxidative stress. Therefore, this paradigm of binge ethanol exposure caused a spectrum of tissue injury and cellular stress to the pancreas, offering a good model to study alcoholic pancreatitis.
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PMID:Binge ethanol exposure causes endoplasmic reticulum stress, oxidative stress and tissue injury in the pancreas. 2752 70